Highly pathogenic notifiable avian influenza (HPNAI) is a disease caused by influenza A virus. It is frequently fatal in poultry. Since late 2003, disease outbreaks caused by the Asian strains of HPAI H5N1 virus have ravaged the poultry industry with the death of over 200 million birds. The epidemic has spread from Asia to Europe and more recently to Africa. To date, more than 200 human fatalities have occurred. A clear understanding of the full epidemiology of the disease at the genetic and spatial/temporal level is critical for the management, control and eventual eradication of the virus. In this study, modern tools of molecular epidemiology (Reverse-transcriptase polymerase chain reaction (RT-PCR), molecular characterization and phylogenetic analyses), Geographical Information Systems (GIS) and remote sensing, and other epidemiological tools were used to explore the outbreak of HPNAI in Nigeria. The molecular and spatial analyses both concluded that Nigeria was infected with multiple infections. The spread of primary outbreaks, which affected mainly sectors 2 and 3 of the poultry industry as described by Food and Agricultural Organisation of the United Nations, were strongly linked to trades, live bird markets, inappropriate disposal of carcasses and poorly implemented control measures. This work did not find a strong correlation between wild birds and HPNAI H5N1 in Nigeria. Some of the analyzed viruses showed genetic drift, and the implications of these for future epidemiology and ecology of avian influenza in Africa will need further evaluation. The option of vaccination and its implications were adjudged good, and its shortcomings were highlighted. Community initiative at fighting emergency diseases like HPNAI H5N1 was similarly advocated. The financial losses to the Nigerian poultry industry were estimated at around $680 million. The risk of the spread of infection was assessed using ecological niche modeling and the whole of West Africa is at risk of infection, should no concrete action be taken to halt the spread. In conclusion, useful suggestions were proffered to affected countries like Nigeria, and unaffected countries that are at risk of infection, so that Africa can be safe from the scourge of HPNAI H5N1.